Extracellular Matrix Tissue Prostheses

ABSTRACT

Tissue prostheses having a base structure and a physiological sensor system. The tissue prostheses are adapted and configured to induce remodeling of damaged tissue and regeneration of new tissue and concurrently detect and monitor physiological characteristics when implanted in the subject.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No. 16/369,174, filed on Mar. 29, 2019, which is a continuation of U.S. application Ser. No. 15/652,566, filed on Jul. 18, 2017, which is a continuation of U.S. application Ser. No. 14/571,639, filed on Dec. 16, 2014, now U.S. Pat. No. 9,744,264, which is a division of U.S. application Ser. No. 13/896,424, filed on May 17, 2013, now U.S. Pat. No. 9,283,302, which is a continuation-in-part of U.S. application Ser. No. 13/573,566, filed on Sep. 24, 2012, now U.S. Pat. No. 9,066,993, which is a continuation-in-part of U.S. application Ser. No. 13/328,287, filed on Dec. 16, 2011, now U.S. Pat. No. 9,532,943.

FIELD OF THE INVENTION

The present invention relates to methods and apparatus for repairing damaged or diseased biological structures. More particularly, the present invention relates to tissue prostheses for treating and/or reconstructing damaged or diseased biological structures; particularly, cardiovascular structures.

BACKGROUND OF THE INVENTION

As is well known in the art, various prostheses are often employed to treat and reconstruct damaged or diseased biological structures and associated tissue, such as cardiovascular vessels and heart tissue. However, despite the growing sophistication of medical technology, the use of prostheses to treat or replace damaged biological tissue remains a frequent and serious problem in health care. The problem is often associated with the materials employed to construct the prostheses.

As is also well known in the art, the optimal prosthesis material should be chemically inert, non-carcinogenic, capable of resisting mechanical stress, capable of being fabricated in the form required and sterilizable. Further, the material should be resistant to physical modification by tissue fluids, and not excite an adverse inflammatory reaction, induce a state of allergy or hypersensitivity, or, in some cases, promote visceral adhesions.

Various materials and/or structures have thus been employed to construct prostheses that satisfy the aforementioned optimal characteristics. Such materials and structures include tantalum gauze, stainless mesh, Dacron®, Orlon®, Fortisan®, nylon, knitted polypropylene (e.g., Marlex®), microporous expanded-polytetrafluoroethylene (e.g., Gore-Tex®), Dacron reinforced silicone rubber (e.g., Silastlc®), polyglactin 910 (e.g., Vicryl®), polyester (e.g., Mersilene®), polyglycolic acid (e.g., Dexon®), processed sheep dermal collagen, crosslinked bovine pericardium (e.g., Peri-Guard®), and preserved human dura (e.g., Lyodura®).

As discussed in detail below, although some of the noted conventional prosthesis materials satisfy some of the aforementioned optimal characteristics, few, if any, satisfy all of the optimal characteristics.

Metallic mesh structures, e.g., stainless steel meshes, are generally inert and resistant to infection. Metallic mesh structures are, however, prone to fragmentation, which can, and in many instances will, occur after the first year of administration.

Synthetic mesh structures are easily molded and, except for nylon, retain their tensile strength in or on the body. Synthetic mesh structures are, however, typically non-resorbable and susceptibility to infection.

A major problem associated with Marlex®, i.e. polypropylene, mesh structures is that with scar contracture, polypropylene mesh structures become distorted and separate from surrounding normal tissue.

A major problem associated with Gore-Tex®, i.e. polytetrafluoroethylene, mesh structures is that in a contaminated wound it does not allow for any macromolecular drainage, which limits treatment of infections.

In an effort to address the numerous disadvantages associated with the above noted conventional prostheses, xenograft tissue prostheses comprising decellularized extracellular matrix (ECM) have recently been developed and employed to treat and reconstruct damaged or diseased biological structures and associated tissue.

In contrast to the above noted conventional prostheses, decellularized xenograft tissue ECM prostheses have the capacity to remodel, i.e. form biological structures similar to native valve structures when implanted in a subject. Decellularized xenograft tissue ECM prostheses also have the capacity to modulate, i.e. abate or reduce, inflammation of damaged tissue of a biological structure, and induce remodeling of the damaged tissue and regeneration of new tissue, when implanted in a subject.

Although decellularized xenograft ECM tissue prostheses substantially reduce and, in most instances, eliminate the major disadvantages and drawbacks associated with conventional prostheses, there still remains a need to monitor seminal biological parameters or characteristics, e.g., contractility, of a subject in order to assess the recovery progress, e.g., regeneration of new tissue, the presence of complications, etc., after delivery of an ECM tissue prosthesis to a damaged biological structure.

The above noted need can be addressed via one or more of the myriad of available conventional sensor systems and associated methods for monitoring seminal biological parameters or characteristics. There are, however, several significant drawbacks and disadvantages associated with the conventional methods.

A major drawback associated with conventional sensor systems and associated methods is that conventional sensor systems are typically configured to monitor a single biological characteristic, e.g., pulse rate.

A further drawback associated with conventional sensor systems and associated methods is that the sensor systems are typically configured to monitor a biological characteristic, e.g., cardiac pre-load, externally.

A further drawback associated with conventional sensor systems is that such systems typically comprise one or more of the aforementioned polymeric and/or metallic materials. Thus, when such systems are implanted in a subject, the systems can, and in many instances will, induce adverse side effects, e.g., inflammation and infection.

Additional drawbacks associated with conventional sensor systems are that such systems typically comprise a rigid mechanical structure, which is often difficult to couple to soft, dynamic tissue structures, and bulky internal power systems that increase the size of the system and limits system life.

There is thus a need to provide tissue prostheses and, in particular, ECM tissue prostheses, which substantially reduce or eliminate the harsh biological responses associated with conventional polymeric and metal prostheses, and the formation of biofilm, inflammation and infection, when implanted in a subject, i.e. delivered to damaged tissue.

There is also a need to provide sensor systems that are capable of accurately monitoring seminal physiological characteristics of a subject over extended periods of time without inducing harsh biological responses when implanted in a subject's body.

It is therefore an object of the present invention to provide tissue structures or prostheses that substantially reduce or eliminate the harsh biological responses associated with conventional polymeric and metal prostheses, and the formation of biofilm, inflammation and infection, when implanted in a subject.

It is another object of the present invention to provide sensor systems that are capable of accurately monitoring seminal physiological characteristics of a subject over extended periods of time without inducing harsh biological responses when implanted in a subject's body.

It is another object of the present invention to provide tissue prostheses that remodel and modulate inflammation of damaged tissue, and induce host tissue proliferation, remodeling of the damaged tissue and regeneration of new tissue and tissue structures, when implanted in a subject, i.e. delivered to the damaged tissue.

It is another object of the present invention to provide tissue prostheses, which, when implanted in a subject, remodel, modulate inflammation of damaged tissue, and induce remodeling of the damaged tissue and regeneration of new tissue and tissue structures, and accurately monitor physiological characteristics of the subject.

SUMMARY OF THE INVENTION

The present invention is directed to tissue prostheses, which, when implanted in a subject, treat and/or reconstruct damaged or diseased biological structures and monitor seminal physiological characteristics.

In a preferred embodiment, the tissue prostheses of the invention comprise a base structure and a physiological sensor system.

In some embodiments, the base structure comprises a prosthetic sheet structure.

In some embodiments, the sheet structure comprises at least one sheet or layer.

In some embodiments, the sheet structure comprises multiple sheets or layers.

In some embodiments, the base structure comprises a prosthetic valve structure.

In some embodiments, the base structure comprises a prosthetic vascular structure.

In a preferred embodiment, the base structure comprises an ECM composition comprising acellular or decellularized ECM derived from a mammalian tissue source.

Preferably, the mammalian tissue source is selected from the group comprising small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, gastrointestinal tissue, i.e. large and small intestines, placental tissue, cardiac tissue, e.g., pericardium and/or myocardium, kidney tissue, pancreas tissue, lung tissue, and combinations thereof.

In some embodiments of the invention, the ECM composition includes at least one additional biologically active agent or composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

In some embodiments of the invention, the biologically active agent comprises a growth factor.

In some embodiments of the invention, the biologically active agent comprises a cell.

In some embodiments, the ECM composition includes at least one pharmacological agent or composition (or drug), i.e. an agent or composition that is capable of producing a desired biological effect in vivo, e.g., stimulation or suppression of apoptosis, stimulation or suppression of an immune response, etc.

In some embodiments of the invention, the pharmacological agent comprises an anti-inflammatory agent or composition.

In some embodiments, the base structure comprises an ECM-mimicking composition.

In some embodiments, the ECM-mimicking composition comprises poly(glycerol sebacate) (PGS).

In some embodiments, the base structure comprises an ECM/PGS composition comprising acellular ECM and PGS.

In some embodiments, base structure comprises a polymeric composition comprising at least one biodegradable or bioresorbable polymer including, without limitation, polylactic acid (PLA), poly(DL-lactide-co-caprolactone), poly(lactic co-glycolic acid), poly-D,L lactide, poly-l-lactic acid, polycaprolactone (PCL), poly(ester-amide), L-lactide/DL-lactide (PLDL), L-lactide/D-lactide (PLD), L-lactide/glycolide (PLG), L-lactide/caprolactone (PLC), DL-lactide/glycolide (PDLG), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(glycerol sebacate) (PGS), Artelon® (polyurethane urea), poly(ortho esters), poly(phosphoesters), poly(anhydrides), poly(carbonates), poly-(R)-3-hydroxybutyrate (P3HB), Polyhydroxybutyrate (PHB), Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), Polydioxanone (PDO, PDS), poly(trimethylene carbonate), poly(acrylates), poly(ethylene glycol) (PEG), poly(acetals), poly(ortho esters), polyphosphazenes, polyamides, collagen, silk, gelatin, hyaluronic acid, cross-linked biological tissue and derivatives thereof, cellulose, chitin, chitosan, alginates, dextran, pullulan, cyclodextrin and combinations thereof.

In a preferred embodiment, the physiological sensor system is configured to detect and measure at least one physiological event associated with a monitored subject or physical aspect of a local environment when disposed proximate thereto.

In some embodiments of the invention, the physiological sensor system comprises sensor means, processing means, signal transmitting means and power supply means.

In a preferred embodiment, the sensor means is configured to detect and measure at least one of the following physiological characteristics in vivo: tissue contractility, vascular contractility, tissue action potential, electrical activity, i.e. EKG, blood fluid rate, blood pressure, fluid pH, blood oxygen content and immune response.

In some embodiments, the power supply means comprises an energy harvesting system.

In a preferred embodiment of the invention, when a tissue prosthesis of the invention is implanted in a subject proximate damaged tissue, the base structure remodels, modulates inflammation of the damaged tissue, and concurrently induces remodeling of the damaged tissue and regeneration of new tissue and tissue structures, and the physiological sensor system monitors physiological characteristics of the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which:

FIG. 1 is a schematic illustration of one embodiment of a physiological sensor system, in accordance with the invention;

FIG. 2 is a perspective view of one embodiment of an energy harvesting system, in accordance with the invention;

FIG. 3 is a schematic illustration of another embodiment of a physiological sensor system, in accordance with the invention;

FIG. 4 is an illustration of a human heart, showing the pulmonary and systemic circulation sections;

FIG. 5 is a graphical illustration of a cardiac cycle, showing cardiac events and changes in blood volume and pressure associated therewith;

FIG. 6 is a graphical illustration of a cardiac cycle represented by anatomical acceleration and velocity over time, in accordance with the invention;

FIG. 7 is a perspective view of one embodiment of a sheet structure incorporating one embodiment of a physiological sensor sub-system, in accordance with the invention;

FIG. 8 is a front sectional plan view of the sheet structure shown in FIG. 1, in accordance with the invention;

FIG. 9 is a side view of another embodiment of a sheet structure incorporating one embodiment of a physiological sensor system, in accordance with the invention;

FIG. 10 is a perspective view of one embodiment of a micro-needle sheet structure incorporating one embodiment of a physiological sensor system, in accordance with the invention;

FIG. 11 is a perspective view of one embodiment of a laminate sheet structure incorporating one embodiment of a physiological sensor system, in accordance with the invention;

FIG. 12 is a side view of the laminate sheet structure shown in FIG. 11, showing the physiological sensor system disposed therebetween, in accordance with the invention;

FIG. 13 is a side view of the laminate sheet structure shown in FIGS. 11 and 12, having laminated ends, in accordance with the invention;

FIG. 14A is a perspective view of one embodiment of a two-piece prosthetic tissue valve member, incorporating one embodiment of a physiological sensor system, in accordance with the invention;

FIG. 14B is a side plan, sectional view of an assembled two-piece prosthetic tissue valve member having one embodiment of a physiological sensor system disposed in an internal region of the valve member, in accordance with the invention;

FIG. 15A is a perspective sectional view of a seamless prosthetic tissue valve member having one embodiment of a physiological sensor system disposed in an internal region of the valve member, in accordance with the invention;

FIG. 15B is a perspective partial sectional view of the seamless prosthetic tissue valve member shown in FIG. 15A showing the formed valve leaflets in a closed configuration, in accordance with the invention; and

FIG. 16 is a perspective view of a conical prosthetic tissue valve member having one embodiment of a physiological sensor system disposed in an internal region of the valve member, in accordance with the invention;

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified apparatus, systems, structures or methods as such may, of course, vary. Thus, although a number of apparatus, systems and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred apparatus, systems, structures and methods are described herein.

It is understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

As used in this specification and the appended claims, the singular forms “a, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “an active” includes two or more such actives and the like.

Further, ranges can be expressed herein as from “about” or “approximately” one particular value, and/or to “about” or “approximately” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about” or “approximately”, it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” or “approximately” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “approximately 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed then “less than or equal to 10” as well as “greater than or equal to 10” is also disclosed.

Definitions

The term “medical device”, as used herein, means and includes any device configured (i) for insertion or implantation in the body of a warm blooded mammal, including humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like, and (ii) to communicate with a biological structure in the body of the warm blooded mammal, e.g., modulate or assist a biological function, such as pulse rate, and/or detect and measure a physiological parameter or characteristic. The term “medical device” thus includes, without limitation, a pacemaker, defibrillator, synthetic heart valve, ventricular assist device, artificial heart, physiological sensor, catheter, and associated components thereof.

The term “sensor” and “physiological sensor” are used interchangeably herein and mean and include an apparatus or system that is configured to detect, measure and/or monitor a physiological characteristic or parameter of a subject.

The terms “sensor” and “physiological sensor” thus mean and include, without limitation, the following sensors: micro-electro-mechanical systems (MEMs) sensors (e.g., piezoelectric sensors), capacitive cantilever sensors, accelerometers, fluid pressure sensors, contact sensors, position sensors, pulse pressure sensors, capacitive pressure sensors, blood volume sensors, blood flow sensors, chemistry sensors (e.g., for blood and/or other fluids), metabolic sensors (e.g., for blood and/or other fluids), ion sensitive field-effect transistor (FET) sensors, immuno-sensors, mechanical stress sensors, capacitive membrane pressure sensors, capacitive angular speed sensors, temperature sensors, magnetic sensors and the like.

The term “signal”, as used herein, is meant to mean and include, without limitation, an analog electrical waveform or a digital representation thereof, which is collected or transmitted by a biological or physiological sensor, such as a photoplethysmographic tissue probe or electrocardiogram.

The term “cardiac cycle”, as used herein, is meant to mean and include, without limitation, a sequence of contractions (systole), which results in an increase in pressure and expelling of blood into the arteries, and relaxations (diastole), which results in a decrease in pressure and the filling of the heart chambers from the veins.

The term “pre-ejection period”, as used herein, is meant to mean and include the time from the onset of the QRS to the opening of the aortic valve during the cardiac cycle.

The term “stroke volume”, as used herein, is meant to mean and include, without limitation, a measure of volume pumped per heartbeat, which is typically expressed as the volume of blood pumped from a ventricle of the heart in one beat.

The term “cardiac output”, as used herein, is meant to mean and include, without limitation, a measure of the volume of blood pumped per unit of time, which is typically expressed as the volume of blood ejected from the left side of the heart in one minute, in units of liters per minute (l/min).

The term “cardiac index”, as used herein, is meant to mean and include, without limitation, a cardiodynamic measure based on the cardiac output. Cardiac index is typically expressed as the amount of blood the left ventricle ejects into the systemic circulation in one minute, divided by the body surface area (“BSA”), i.e. the total surface area of the human body. The cardiac index typically has units of (l/min)/m².

The term “systolic blood pressure”, as used herein, is meant to mean and include, without limitation, peak pressure in the arteries, which occurs near the end of the cardiac cycle when the ventricles are contracting.

The term “diastolic blood pressure”, as used herein, is meant to mean and include, without limitation, minimum pressure in the arteries, which occurs near the beginning of the cardiac cycle when the ventricles are filled with blood.

The term “mean arterial pressure (MAP)”, as used herein, is meant to mean and include, without limitation, the average pressure within an artery over a complete cycle of one heartbeat.

The term “blood volume”, as used herein, is meant to mean and include, without limitation, the total amount of blood in the body.

The term “perfusion”, as used herein, is meant to mean and include, without limitation, the passage of blood through one or more organs or tissues of the body.

The term “oxygen delivery”, as used herein, is meant to mean and include, without limitation, the amount of oxygen carried by the blood and delivered to one or more organs or tissues of the body.

The term “oxygen extraction”, as used herein, is meant to mean and include, without limitation, the amount of oxygen extracted from the blood by one or more organs or tissues.

The term “systemic vascular resistance”, as used herein, is meant to mean and include, without limitation, an index of arteriolar constriction throughout the body.

The term “stenosis”, as used herein, is meant to mean and include, without limitation, an abnormal narrowing in one or more areas of the vasculature of the body.

The term “cardiac performance”, as used herein, is meant to mean a functional characteristic of the heart and associated cardiovascular system, including, without limitation, the aforementioned stroke volume, cardiac output and cardiac index. The term “cardiac performance” further means and includes, without limitation, systemic vascular resistance, perfusion, degree of stenosis, blood volume, mean arterial pressure, systolic blood pressure, diastolic blood pressure, hematocrit, oxygen extraction, and oxygen delivery.

The terms “extracellular matrix” and “ECM” are used interchangeably herein, and mean and include a collagen-rich substance that is found in between cells in mammalian tissue, and any material processed therefrom, e.g., decellularized or acellular ECM.

According to the invention, the ECM can be derived from a variety of mammalian tissue sources, including, without limitation, small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, dermal tissue, gastrointestinal tissue, i.e. large and small intestine tissue, placental tissue, omentum tissue, cardiac tissue, e.g., pericardium and/or myocardium tissue, kidney tissue, pancreas tissue, lung tissue, and combinations thereof.

The ECM can also comprise collagen from mammalian sources.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa (SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/or SIS and/or SS tissue that includes the tunica mucosa (which includes the transitional epithelial layer and the tunica propria), submucosal layer, one or more layers of muscularis, and adventitia (a loose connective tissue layer) associated therewith.

The ECM can also be derived from basement membrane of mammalian tissue/organs, including, without limitation, urinary basement membrane (UBM), liver basement membrane (LBM), and amnion, chorion, allograft pericardium, allograft acellular dermis, amniotic membrane, umbilical cord, Wharton's jelly, and combinations thereof.

Additional sources of mammalian basement membrane include, without limitation, spleen, lymph nodes, salivary glands, prostate, pancreas and other secreting glands.

The ECM can also be derived from other sources, including, without limitation, collagen from plant sources and synthesized extracellular matrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic process involving the growth of new blood vessels from pre-existing blood vessels.

The term “neovascularization”, as used herein, means and includes the formation of functional vascular networks that can be perfused by blood or blood components. Neovascularization includes angiogenesis, budding angiogenesis, intussuceptive angiogenesis, sprouting angiogenesis, therapeutic angiogenesis and vasculogenesis.

The terms “biologically active agent” and “biologically active composition” are used interchangeably herein, and mean and include agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

The terms “biologically active agent” and “biologically active composition” thus mean and include, without limitation, the following growth factors: epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), nerve growth factor (NGF), platelet derived growth factor (PDGF), tumor necrosis factor alpha (TNA-α), and placental growth factor (PLGF).

The terms “biologically active agent” and “biologically active composition” also mean and include, without limitation, human embryonic stem cells, fetal cardiomyocytes, myofibroblasts, mesenchymal stem cells, myoblasts, embryonic stem cells and hematopoietic stem cells.

The terms “biologically active agent” and “biologically active composition” also mean and include, without limitation, the following biologically active agents (referred to interchangeably herein as a “protein”, “peptide” and “polypeptide”): collagen (types I-V), proteoglycans, glycosaminoglycans (GAGs), glycoproteins, growth factors, cytokines, cell-surface associated proteins, cell adhesion molecules (CAM), angiogenic growth factors, endothelial ligands, matrikines, cadherins, immuoglobins, fibril collagens, non-fibrallar collagens, basement membrane collagens, multiplexins, small-leucine rich proteoglycans, decorins, biglycans, fibromodulins, keratocans, lumicans, epiphycans, heparin sulfate proteoglycans, perlecans, agrins, testicans, syndecans, glypicans, serglycins, selectins, lecticans, aggrecans, versicans, neurocans, brevicans, cytoplasmic domain-44 (CD-44), macrophage stimulating factors, amyloid precursor proteins, heparins, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparin sulfates, hyaluronic acids, fibronectins, tenascins, elastins, fibrillins, laminins, nidogen/enactins, fibulin I, fibulin II, integrins, transmembrane molecules, thrombospondins, osteopontins, and angiotensin converting enzymes (ACE).

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” are used interchangeably herein, and mean and include an agent, drug, compound, composition of matter or mixture thereof, including its formulation, which provides some therapeutic, often beneficial, effect. This includes any physiologically or pharmacologically active substance that produces a localized or systemic effect or effects in animals, including warm blooded mammals, humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” thus mean and include, without limitation, antibiotics, anti-arrhythmic agents, anti-viral agents, analgesics, anti-inflammatory agent, anti-neoplastics, anti-spasmodics, modulators of cell-extracellular matrix interactions, proteins, hormones, growth factors, matrix metalloproteinases (MMPS), enzymes and enzyme inhibitors, anticoagulants and/or antithrombotic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides, oligonucleotides, polynucleotides, nucleoproteins, compounds modulating cell migration, compounds modulating proliferation and growth of tissue, and vasodilating agents.

The terms “anti-inflammatory” and “anti-inflammatory agent” are also used interchangeably herein, and mean and include a “pharmacological agent” and/or “active agent formulation”, which, when a therapeutically effective amount is administered to a subject, prevents or treats bodily tissue inflammation i.e. the protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues.

Anti-inflammatory agents thus include, without limitation, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, decanoate, deflazacort, delatestryl, depo-testosterone, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, mesterolone, methandrostenolone, methenolone, methenolone acetate, methylprednisolone suleptanate, momiflumate, nabumetone, nandrolone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxandrolane, oxaprozin, oxyphenbutazone, oxymetholone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, stanozolol, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, testosterone, testosterone blends, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, and zomepirac sodium.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” thus include, without limitation, atropine, tropicamide, dexamethasone, dexamethasone phosphate, betamethasone, betamethasone phosphate, prednisolone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, anecortave acetate, budesonide, cyclosporine, FK-506, rapamycin, ruboxistaurin, midostaurin, flurbiprofen, suprofen, ketoprofen, diclofenac, ketorolac, nepafenac, lidocaine, neomycin, polymyxin b, bacitracin, gramicidin, gentamicin, oyxtetracycline, ciprofloxacin, ofloxacin, tobramycin, amikacin, vancomycin, cefazolin, ticarcillin, chloramphenicol, miconazole, itraconazole, trifluridine, vidarabine, ganciclovir, acyclovir, cidofovir, ara-amp, foscarnet, idoxuridine, adefovir dipivoxil, methotrexate, carboplatin, phenylephrine, epinephrine, dipivefrin, timolol, 6-hydroxydopamine, betaxolol, pilocarpine, carbachol, physostigmine, demecarium, dorzolamide, brinzolamide, latanoprost, sodium hyaluronate, insulin, verteporfin, pegaptanib, ranibizumab, and other antibodies, antineoplastics, anti VEGFs, ciliary neurotrophic factor, brain-derived neurotrophic factor, bFGF, Caspase-1 inhibitors, Caspase-3 inhibitors, α-Adrenoceptors agonists, NMDA antagonists, Glial cell line-derived neurotrophic factors (GDNF), pigment epithelium-derived factor (PEDF), NT-3, NT-4, NGF and IGF-2.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” further mean and include the following Class I-Class V antiarrhythmic agents: (Class Ia) quinidine, procainamide and disopyramide; (Class Ib) lidocaine, phenytoin and mexiletine; (Class Ic) flecainide, propafenone and moricizine; (Class II) propranolol, esmolol, timolol, metoprolol and atenolol; (Class III) amiodarone, sotalol, ibutilide and dofetilide; (Class IV) verapamil and diltiazem) and (Class V) adenosine and digoxin.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” further mean and include, without limitation, the following antibiotics: aminoglycosides, cephalosporins, chloramphenicol, clindamycin, erythromycins, fluoroquinolones, macrolides, azolides, metronidazole, penicillin, tetracyclines, trimethoprim-sulfamethoxazole, gentamycin and vancomycin.

The term “pharmacological composition”, as used herein, means and includes a composition comprising a “pharmacological agent” and/or a “biologically active agent” and/or any additional agent or component identified herein.

The term “therapeutically effective”, as used herein, means that the amount of the “pharmacological composition” and/or “pharmacological agent” and/or “biologically active agent” administered is of sufficient quantity to ameliorate one or more causes, symptoms, or sequelae of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination, of the cause, symptom, or sequelae of a disease or disorder.

The terms “prevent” and “preventing” are used interchangeably herein, and mean and include reducing the frequency or severity of a disease or condition. The term does not require an absolute preclusion of the disease or condition. Rather, this term includes decreasing the chance for disease occurrence.

The terms “treat” and “treatment” are used interchangeably herein, and mean and include medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. The terms include “active treatment”, i.e. treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and “causal treatment”, i.e. treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.

The terms “treat” and “treatment” further include “palliative treatment”, i.e. treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder, “preventative treatment”, i.e. treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder, and “supportive treatment”, i.e. treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

The terms “patient” and “subject” are used interchangeably herein, and mean and include warm blooded mammals, humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the term, such as “comprising” and “comprises,” means “including, but not limited to” and is not intended to exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enabling fashion the best modes of performing one or more embodiments of the present invention. The disclosure is further offered to enhance an understanding and appreciation for the inventive principles and advantages thereof, rather than to limit in any manner the invention. The invention is defined solely by the appended claims, including any amendments made during the pendency of this application, and all equivalents of those claims as issued.

As discussed in detail herein, the present invention is directed to tissue prostheses, which, when implanted in a subject, treat and/or reconstruct damaged or diseased biological structures and monitor seminal physiological characteristics of the subject.

Although the tissue prostheses of the invention are described primarily in connection with treating and/or reconstructing damaged or diseased cardiovascular structures and associated tissue and monitoring physiological characteristics associated therewith, it is understood that the tissue prostheses are not limited to treating and/or reconstructing damaged or diseased cardiovascular structures and associated tissue and monitoring physiological characteristics associated therewith.

As one having ordinary skill in the art will readily appreciate, the tissue prostheses of the invention can also be readily employed to treat and/or reconstruct other damaged or diseased cardiovascular structures and associated tissue, e.g., gastrointestinal, respiratory, urinary systems, and monitor physiological characteristics associated therewith.

As indicated above, in a preferred embodiment, the tissue prostheses of the invention comprise a base structure and an integral physiological sensor system.

In some embodiments, the base structure comprises a prosthetic sheet structure.

In some embodiments, the sheet structure comprises at least one sheet or layer.

In some embodiments, the prosthetic sheet structure comprises multiple sheets or layers.

In some embodiments, the base structure comprises a prosthetic vascular structure.

In some embodiments, the base structure comprises a prosthetic valve structure.

In a preferred embodiment, the base structure comprises an ECM composition comprising ECM derived from a mammalian tissue source.

According to the invention, the ECM can be derived from various mammalian tissue sources and methods for preparing same, such as disclosed in U.S. Pat. Nos. 7,550,004, 7,244,444, 6,379,710, 6,358,284, 6,206,931, 5,733,337 and 4,902,508 and U.S. application Ser. No. 12/707,427; which are incorporated by reference herein in their entirety.

In a preferred embodiment, the mammalian tissue sources include, without limitation, small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, dermal tissue, gastrointestinal tissue, i.e. large and small intestine tissue, placental tissue, omentum tissue, cardiac tissue, e.g., pericardium and/or myocardium tissue, kidney tissue, pancreas tissue, lung tissue, and combinations thereof. The ECM can also comprise collagen from mammalian sources.

The ECM can also be derived from the same or different mammalian tissue sources, as disclosed in Co-Pending application Ser. Nos. 13/033,053 and 13/033,102, now U.S. Pat. No. 8,758,448; which are incorporated by reference herein.

In a preferred embodiment, the ECM comprises acellular (or decellularized) ECM, more preferably, the ECM comprises sterilized, acellular ECM.

According to the invention, the ECM can be sterilized via applicant's proprietary sterilization (i.e. Novasterilis®) process, as disclosed in Co-Pending U.S. application Ser. No. 13/480,205; which is expressly incorporated herein in its entirety.

In some embodiments, the base structure comprises an ECM-mimicking composition.

In some embodiments, the ECM-mimicking composition comprises poly(glycerol sebacate) (PGS).

In some embodiments, the ECM-mimicking composition further comprises at least one of the aforementioned biologically active agents and/or pharmacological agents.

In some embodiments, the ECM-mimicking composition is configured to crosslink, i.e. cure, when the ECM-mimicking composition is exposed to radiation.

In some embodiments, the ECM-mimicking composition comprises a photoinitiator to facilitate the crosslinking or curing of the ECM-mimicking composition.

According to the invention, suitable photoinitiators for radiation induced crosslinking comprise, without limitation, 2-hydroxy-1-[4-hydroxyethoxy) phenyl]-2-methyl-1-propanone (D 2959, Ciba Geigy), 2,2-dimethoxy-2-phenylacetophenone, titanocenes, fluorinated diaryltitanocenes, iron arene complexes, manganese decacarbonyl, methylcyclopentadienyl manganese tricarbonyl and any organometallatic photoinitiator that produces free radicals or cations.

According to the invention, suitable radiation wavelengths for crosslinking and/or curing the ECM-mimicking composition comprise, without limitation, visible light; particularly, radiation in the range of approximately 380-750 nm, and ultraviolet (UV) light, particularly, radiation in the range of 10-400 nm, which includes extreme UV (10-121 nm), vacuum UV (10-200 nm), hydrogen lyman α-UV (121-122 nm), Far UV (122-200 nm), Middle UV (200-300 nm), Near UV (300-400 nm), UV-C (100-280 nm), UV-B (280-315 nm) and UV-A (315-400 nm) species of UV light.

In some embodiments, the base structure comprises an ECM/PGS composition comprising acellular ECM and PGS.

As set forth in U.S. Pat. No. 10,143,778, which is incorporated by reference herein, PGS provides numerous beneficial structural and biochemical actions or activities when an ECM-mimicking composition and/or ECM/ECM-mimicking composition and, hence, base structure formed therefrom, is disposed proximate damaged tissue.

In some embodiments, when a base structure is disposed proximate damaged biological tissue, modulated healing is effectuated through the structural features of the base structure. The structural features of the base structure provide the spatial and mechanical cues to modulate endogenous cell polarity and alignment. The structural features of the cardiovascular base structure further modulate endogenous cell proliferation, migration and differentiation.

In some embodiments, base structure comprises a polymeric composition.

According to the invention, the polymeric composition can comprise at least one biodegradable or bioresorbable polymer including, without limitation, polylactic acid (PLA), poly(DL-lactide-co-caprolactone), poly(lactic co-glycolic acid), poly-D,L lactide, poly-l-lactic acid, polycaprolactone (PCL), poly(ester-amide), L-lactide/DL-lactide (PLDL), L-lactide/D-lactide (PLD), L-lactide/glycolide (PLG), L-lactide/caprolactone (PLC), DL-lactide/glycolide (PDLG), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(glycerol sebacate) (PGS), Artelon® (polyurethane urea), poly(ortho esters), poly(phosphoesters), poly(anhydrides), poly(carbonates), poly-(R)-3-hydroxybutyrate (P3HB), Polyhydroxybutyrate (PHB), Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), Polydioxanone (PDO, PDS), poly(trimethylene carbonate), poly(acrylates), poly(ethylene glycol) (PEG), poly(acetals), poly(ortho esters), polyphosphazenes, polyamides, collagen, silk, gelatin, hyaluronic acid, cross-linked biological tissue and derivatives thereof, cellulose, chitin, chitosan, alginates, dextran, pullulan, cyclodextrin and combinations thereof.

In some embodiments, the polymeric composition comprises a hydrogel composition, including, without limitation, polyurethane, poly(ethylene glycol), poly(propylene glycol), poly(vinylpyrrolidone), xanthan, methyl cellulose, carboxymethyl cellulose, alginate, hyaluronan, poly(acrylic acid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl cellulose, methacrylic acid, αβ-glycerophosphate, κ-carrageenan, 2-acrylamido-2-methylpropanesulfonic acid, and β-hairpin peptide.

In some embodiments, the base structure comprises an ECM/polymeric composition comprising acellular ECM and at least one of the aforementioned polymers.

As stated above, in some embodiments of the invention, the ECM compositions (and/or ECM-mimicking compositions and/or ECM/PGS compositions and/or polymeric compositions and/or ECM/polymeric compositions), hence, base structures formed therefrom include at least one additional biologically active agent or composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

Suitable biologically active agents include any of the aforementioned biologically active agents, including, without limitation, the aforementioned cells, proteins and growth factors.

In some embodiments, the supplemental biologically active agent comprises an exogenous exosome. Thus, in some embodiments of the invention, the ECM compositions (and/or ECM-mimicking compositions and/or ECM/PGS compositions and/or polymeric compositions and/or ECM/polymeric compositions) and, hence, base structures formed therefrom comprises a plurality of exogenous exosomes. ECM, polymeric, ECM-mimicking, ECM/PGS and ECM/polymeric compositions comprising an exosome are hereinafter referred to as exosome augmented compositions.

As indicated above, exosomes comprise a lipid bilayer structure that contains or encapsulates a biologically active agent, such as a growth factor, e.g., TGF-β, TGF-α, VEGF and insulin-like growth factor (IGF-I), cytokine, e.g., interleukin-8 (IL-8), transcription factor and micro RNA (miRNA).

As set forth in U.S. Pat. No. 10,143,778, which is incorporated by reference herein, exosomes significantly enhance the delivery of biologically active agents to cells through two seminal properties/capabilities. The first property comprises the capacity of exosomes to shield the encapsulated biologically active agents (via the exosome lipid bilayer) from proteolytic agents, which can, and often will, degrade unshielded (or free) bioactive molecules and render the molecules non-functional in biological tissue environments.

The second property of exosomes comprises the capacity to directly and, hence, more efficiently deliver biologically active agents to endogenous cells in the biological tissue. As is well known in the art, endogenous cells typically do not comprise the capacity to “directly” interact with “free” biologically active agents, such as growth factors. There must be additional biological processes initiated by the endogenous cells to interact directly with biologically active agents, e.g., expression of receptor proteins for or corresponding to the biologically active agents.

Exosomes facilitate direct interaction by and between endogenous cells and exosome encapsulated biologically active agents (and, hence, direct delivery of bioactive molecules to endogenous cells), which enhances the bioactivity of the agents.

According to the invention, when an exosome composition comprises acellular ECM and the exosome augmented composition is delivered to the damaged biological tissue, the noted exosome augmented ECM composition “concomitantly” induces a multitude of significant biological processes in vivo, including (i) significantly enhanced inflammation modulation of the damaged biological tissue, (ii) induced neovascularization, (iii) induced stem cell proliferation, (iv) induced remodeling of the damaged biological tissue, and (v) induced regeneration of new tissue and tissue structures with site-specific structural and functional properties, compared to acellular ECM alone.

By way of example, when an exosome augmented ECM composition comprising encapsulated IL-8 (and, hence, base structure formed therefrom) is disposed proximate damaged biological tissue, the exosome encapsulated IL-8 and, hence, tissue prosthesis modulates the transition of M type “acute inflammatory” macrophages to M2 type “wound healing” macrophages initiated by the acellular ECM.

By way of further example, when an exosome augmented ECM composition comprising encapsulated miRNAs (and, hence, base structure formed therefrom) is disposed proximate damaged biological tissue, the base structure induces enhanced stem cell proliferation via the delivery of exosome encapsulated miRNAs and transcription factors to the damaged biological tissue, which signals the endogenous stem cells to bind and/or attach to the acellular ECM and proliferate.

In some embodiments, the exosomes are derived and, hence, processed from an aforementioned tissue source. In some embodiments, the exosomes are processed and derived from a mammalian fluid composition including, but not limited to blood, amniotic fluid, lymphatic fluid, interstitial fluid, pleural fluid, peritoneal fluid, pericardial fluid and cerebrospinal fluid.

In some embodiments, exosomes are derived and, hence, processed from in vitro or in vivo cultured cells. According to the invention, exosomes can be derived from any one of the aforementioned cells, such as mesenchymal stem cells and hematopoietic stem cells.

In some embodiments, mesenchymal stem cells are cultured in a cell culture media under hypoxic conditions to induce a higher production rate of exosomes.

In some embodiments, mesenchymal stem cells are cultured on an aforementioned acellular ECM, where the mesenchymal stem cells condition the acellular ECM by releasing exosomes, which bind to the ECM composition to form an exosome augmented ECM composition and/or ECM/PGS composition and/or ECM/polymeric composition.

In some embodiments, the exosomes comprise semi-synthetically generated exosomes. According to the invention, the semi-synthetically generated exosomes can be derived from an exosome producing cell line.

By way of example, semi-synthetically generated exosomes can be generated by incubating mesenchymal stem cells in a medium comprising a predetermined concentration of any one of the aforementioned biologically active agents and/or pharmacological active agents and, after a predetermined period of time, removing the mesenchymal stem cells from the incubating medium and in vitro culturing using conventional cell culture techniques. The cell culture media employed can then be processed to isolate one or more exosome-encapsulated biologically active agents and/or pharmacological active agents.

According to the invention, the exosome-encapsulated biologically active agents and/or pharmacological active agents can be isolated from the cell culture media using any known conventional method, such as ultra-centrifugation.

According to the invention, the semi-synthetically generated exosomes markedly improve the efficacy of the aforementioned biologically active agents and/or the pharmacological active agents by providing a means of traversing the cell membrane of endogenous cells.

In some embodiments, the ECM compositions (and/or ECM-mimicking compositions and/or ECM/PGS compositions and/or polymeric compositions and/or ECM/polymeric compositions), hence, base structures formed therefrom include at least one pharmacological agent or composition (or drug), i.e. an agent or composition that is capable of producing a desired biological effect in vivo, e.g., stimulation or suppression of apoptosis, stimulation or suppression of an immune response, etc.

Suitable pharmacological agents and compositions include any of the aforementioned agents, including, without limitation, antibiotics, anti-viral agents, analgesics, steroidal anti-inflammatories, non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics, modulators of cell-extracellular matrix interactions, proteins, hormones, enzymes and enzyme inhibitors, anticoagulants and/or antithrombotic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides, oligonucleotides, polynucleotides, nucleoproteins, compounds modulating cell migration, compounds modulating proliferation and growth of tissue, and vasodilating agents.

In some embodiments of the invention, the pharmacological agent comprises an anti-inflammatory agent.

In some embodiments of the invention, the pharmacological agent comprises a statin, i.e. a HMG-CoA reductase inhibitor. According to the invention, suitable statins include, without limitation, atorvastatin (Lipitor®), cerivastatin, fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), mevastatin, pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®). Several actives comprising a combination of a statin and another agent, such as ezetimbe/simvastatin (Vytorin®), are also suitable.

As also set forth in U.S. Pat. No. 10,143,778, which is incorporated herein in its entirety, when an ECM composition comprising acellular ECM and a statin; particularly, cerivastatin, i.e. a statin augmented ECM composition, is disposed (i.e. delivered or administered) proximate damaged biological tissue, the statin augmented ECM composition also induces several beneficial biochemical actions or activities, which enhance modulated healing.

Further details regarding the beneficial biochemical actions or activities induced when a statin augmented ECM composition is disposed to biological tissue are set forth in U.S. Pat. Nos. 9,119,899, 9,072,816 and 9,044,319, which are incorporated by reference herein in their entirety.

Significant biochemical action that is induced when a statin augmented ECM composition of the invention is disposed proximate damaged biological tissue is restricted expression of MCP-1 and C—C chemokine receptor type 2 (CCR2), which provides an enhanced level of inflammation modulation of the damaged biological tissue.

According to the invention, the amount of a pharmacological agent added to the ECM compositions (and/or ECM-mimicking compositions and/or ECM/PGS compositions and/or polymeric compositions and/or ECM/polymeric compositions) and, hence, base structure of the invention will, of course, vary from agent to agent. For example, in one embodiment, wherein the pharmacological agent comprises dicloflenac (Voltaren®), the amount of dicloflenac included in the ECM composition is preferably in the range of 10 μg-75 mg.

In some embodiments, the ECM compositions (and/or ECM-mimicking compositions and/or ECM/PGS compositions and/or polymeric compositions and/or ECM/polymeric compositions) and, hence, base structure formed therefrom further comprises an antibiotic. ECM, ECM-mimicking, ECM/PGS, polymeric, and ECM/polymeric compositions comprising an antibiotic are hereinafter referred to as antibiotic augmented compositions.

In some embodiments of the invention, the antibiotic augmented compositions preferably comprise vancomycin and/or gentamicin.

As also set forth in U.S. Pat. No. 10,143,778, in some embodiments of the invention, when an antibiotic augmented composition and, hence, base structure formed therefrom is delivered directly, i.e. local delivery, to damaged biological tissue, the antibiotic augmented composition induces several significant biological processes, including anti-microbial and anti-biofilm activity, which significantly enhance modulated healing, including inflammation modulation of the damaged biological tissue.

According to the invention, the biologically active and pharmacological agents referenced above can comprise any form. In some embodiments of the invention, the biologically active and pharmacological agents, e.g., simvastatin, comprise microcapsules that provide delayed delivery of the agent contained therein.

As stated above, in some embodiments of the invention, upon delivery of a tissue prosthesis of the invention; particularly, a tissue prosthesis comprising a base structure comprising an ECM composition or ECM/PGS composition or ECM/polymer composition, to damaged biological tissue, the base structure remodels and induces modulated healing of the damaged tissue.

The phrase “modulated healing”, as used herein, and variants of this language generally refer to the modulation (e.g., alteration, delay, retardation, reduction, etc.) of a process involving different cascades or sequences of naturally occurring tissue repair in response to localized tissue damage or injury, substantially reducing their inflammatory effect. Modulated healing, as used herein, includes many different biologic processes, including epithelial growth, fibrin deposition, platelet activation and attachment, inhibition, proliferation and/or differentiation, connective fibrous tissue production and function, angiogenesis, and several stages of acute and/or chronic inflammation, and their interplay with each other.

In some embodiments, the tissue prosthesis, i.e. base structure, is specifically formulated (or designed) to alter, delay, retard, reduce, and/or detain one or more of the phases associated with healing of damaged tissue, including, but not limited to, the inflammatory phase (e.g., platelet or fibrin deposition), and the proliferative phase.

In some embodiments, “modulated healing” refers to the ability of a tissue prosthesis, i.e. base structure, of the invention to alter a substantial inflammatory phase (e.g., platelet or fibrin deposition) at the beginning of the tissue healing process. As used herein, the phrase “alter a substantial inflammatory phase” refers to the ability of a tissue prosthesis to substantially reduce the inflammatory response at an injury site.

In some embodiments of the invention, “modulated healing” refers to the ability of a tissue prosthesis, i.e. base structure, of the invention to induce host tissue proliferation, bioremodeling, including neovascularization, e.g., vasculogenesis, angiogenesis, and intussusception, and regeneration of tissue structures with site-specific structural and functional properties.

In some embodiments of the invention, “modulated healing” also refers to the ability of a tissue prosthesis, i.e. base structure, of the invention to induce anti-microbial and anti-biofilm activity and, thereby, enhanced inflammation modulation of damaged biological tissue, neovascularization and remodeling of the damaged biological tissue and regeneration of new tissue and tissue structures, when the tissue prosthesis is disposed proximate the damaged tissue.

As also indicated above, in a preferred embodiment, the tissue prostheses of the invention further comprise a physiological sensor system that is configured to detect and measure at least one physiological event associated with a monitored subject or physical aspect of a local environment when disposed proximate thereto.

In a preferred embodiment of the invention, the physiological sensor system comprises a biocompatible physiological sensor system.

As discussed below, in some embodiments of the invention, the physiological sensor system comprises a biocompatible and biodegradable physiological sensor system.

Referring now to FIG. 1, there is shown one embodiment of a physiological sensor system of the invention (denoted “100”). As illustrated in FIG. 1, the sensor system 100 preferably comprises a physiological sensor sub-system 3, comprising sensor means 2, processing means 4, signal transmitting means 6, power supply means 8 and signal transmission conductors 5, and a remote device 12, such as a base module or a hand-held electronic device, e.g., a smart phone, tablet or computer.

According to the invention, the physiological sensor sub-system 3 can comprise any suitable shape and size to accommodate a base tissue structure of the invention. In a preferred embodiment of the invention, the physiological sensor sub-system 3 comprises an area less than 25 mm² and a thickness less than 300 μm.

In a preferred embodiment of the invention, the sensor means 2 is configured to detect and measure at least one of the following physiological characteristics in vivo: tissue contractility, vascular contractility, tissue action potential, electrical activity (i.e. EKG, blood fluid rate, blood pressure, fluid pH, blood oxygen content and immune response.

In a preferred embodiment, the sensor means 2 is further configured to generate sensor signals representing detected physiological events or physical aspects of the local environment and transmit the sensor signals representing same to the processing means 4 via the signal transmission conductors 6.

In some embodiments, the sensor means 2 comprises at least one (1) sensor. In some embodiments, the sensor means 2 comprises a plurality of sensors.

In some embodiments, the sensor means 2 comprises an array of sensors.

In some embodiments, the sensor means 2 comprises a micro-electro-mechanical (MEM) sensor.

According to the invention, the MEM sensor can comprise any suitable MEM sensor including, without limitation, an accelerometer, gyrosensor, a force sensor (e.g., a strain gauge or pressure transducer), mercury pressure sensor, piezoresistive pressure sensor, capacitive pressure sensor, optoelectronic pressure sensor and the like.

In some embodiments, the sensor means 2 comprises a piezoelectric sensor, such as a piezoelectric MEM sensor (piezoMEM).

In a preferred embodiment, the sensor means 2 comprises a MEM accelerometer.

In some embodiments, the processing means 4 of the physiological sensor sub-system 3 is programmed and configured to control the sensor means 2 and the function thereof, and the receipt of signals thereto and transmission of signals therefrom. In a preferred embodiment of the invention, the processing means 4 is configured to process sensor signals received from the sensor means 2 and transmit the processed sensor signals to the signal transmitting means 6 via the signal transmission conductors 5.

In a preferred embodiment of the invention, the processing means 4 comprises a programmable application-specific integrated circuit (ASIC).

In some embodiments, the signal transmitting means 6 of the physiological sensor sub-system 3 is programmed and configured to receive processed sensor signals from the processing means 4 and transmit the processed sensor signals to the remote device 12, e.g., a base module or a hand-held electronic device, such as a smart phone, tablet or computer.

In a preferred embodiment of the invention, the remote device 12 is programmed and configured (i.e. comprises programs, parameters, instructions and at least one algorithm) to control the physiological sensor sub-system 3 and the function thereof, and the receipt of signals thereto and transmission of signals therefrom.

In a preferred embodiment, the remote device 12 is also preferably programmed and configured to (i) receive and process the wireless sensor signals that are generated and transmitted by the signal transmitting means 6 of the physiological sensor system 100, (ii) determine at least one physiological parameter, more preferably, a plurality of physiological parameters associated with the monitored subject as a function of the processed sensor signals and (iii) determine at least one physiological parameter value as a function of the processed sensor signals.

As illustrated in FIG. 1, preferably the remote device 12 further includes display means 14 that is configured to display visual representations of the determined physiological parameters associated with the monitored subject, e.g., electrocardiogram tracing.

As further illustrated in FIG. 1, the physiological sensor sub-system 3 further comprises a power supply means 8 that is configured to supply the physiological sensor sub-system 3 with the necessary power to operate.

In some embodiments, the power supply means 8 comprises a conventional battery, such as a lithium ion battery or a nickel metal hydride battery. In some embodiments, the battery is integral with the physiological sensor sub-system 3.

In some embodiments, the power supply means 8 comprises an energy harvesting system or generator that is configured to generate power for the physiological sensor system 100 by converting mechanical, chemical, electrical or thermal physiological processes into electrical energy.

In some embodiments of the invention, the energy harvesting system includes a back-up energy storage system, such as a battery.

In a preferred embodiment, the energy harvesting system is designed configured to convert biomechanical movements of a monitored subject's biological structures, e.g., myocardial expansions and contractions, movements associated with respiration, e.g., rib cage expansion, and expansion and contraction of various other organ systems, into electrical energy.

In some embodiments, the energy harvesting system comprises a biocompatible piezoelectric film that is configured to convert biomechanical movements of biological structures into electrical power via the piezoelectric effect, including, without limitation, Pb(Zr_(x)Ti_(1−x))O₃ (PZT) ferroelectric perovskite films, piezoelectric ceramic films (e.g., BaTiO₃ films, (Bi,Na)TiO₃ films, BiFeO₃ films and (K,Na)NbO₃ (KNN) films), aluminum nitride (AlN) films, zinc oxide (ZnO) films, piezoelectric polymer films (e.g., polyvinylidene fluoride (PVDF) films and polyvinylidene fluoridetrifluoroethylene (PVDF-TrFE) films).

In some embodiments, the piezoelectric film comprises a lead-free film, such as a (K,Na)NbO₃ (KNN) film.

According to the invention, the piezoelectric film can comprise any film suitable for use in the physiological sensor system 100 (and system 102 discussed below) and, hence, physiological sensor sub-system 3 of the invention, such as the films disclosed in Todaro, et al., Biocompatible, Flexible, and Compliant Energy Harvesters Based on Piezoelectric Thin Films, IEEE Transactions on Nanotechnology, vol. 17, no. 2, pp. 220-230 (2018) and Dagdeviren, et al., Conformal Piezoelectric Energy Harvesting and Storage from Motions of the Heart, Lung, and Diaphragm, PNAS, vol. 111, no. 5, pp. 1927-1932 (2014), which are incorporated by reference herein in their entirety.

In some embodiments, the piezoelectric film comprises a biodegradable film, such as the Poly-L-lactic acid (PLLA) piezoelectric film disclosed in Curry, et al., Biodegradable Piezoelectric Force Sensor, Proceedings of the National Academy of Sciences, vol. 115, pp. 1-6 (2018), which is incorporated by reference herein in its entirety.

In a preferred embodiment of the invention, the biocompatible piezoelectric films of the invention; particularly, the films referenced above, comprise a maximum thickness of approximately 300 μm, more preferably, the biocompatible piezoelectric films comprise a maximum thickness in the range of 150-250 μm.

In some embodiments, the energy harvesting system is designed and configured to convert the thermal gradient by and between the energy harvesting system and any physiological structure disposed proximate thereto into electrical energy.

Referring now to FIG. 2, in some embodiments, the power supply means 8 comprises an energy harvesting thermoelectric coil system 200. As illustrated in FIG. 2, in a preferred embodiment, the thermoelectric coil system 200 comprises a polymer film 204 comprising a plurality of thermoelectric coils 202 embedded therein. According to the invention, the thermoelectric coil system 200 can comprise any number of thermoelectric coils 202.

According to the invention, the thermoelectric coils 202 can comprise any suitable thermoelectric material, such as Bi₂Te₃—Sb₂Te₃ alloys, Zn₄Sb₃, and Cu₂Se.

In some embodiments, the thermoelectric coils 202 comprise a biocompatible and biodegradable thermoelectric material, such as a biodegradable graphene.

According to the invention, the polymer film 204 can comprise any suitable polymeric composition. In some embodiments, the polymeric composition comprises at least one non-biodegradable polymer including, without limitation, poly(tetrafluoroethylene) (PTFE), expanded poly(tetrafluoroethylene) (ePTFE), poly(vinyl chloride) (PVC), poly(dimethylsiloxane) (PDMS), poly(methyl methacrylate) (PMMA), poly(2-hydroxyethyl methacrylate) (pHEMA), poly(ethylene terephthalate) (PET or Dacron®), poly(ethersulfone) (PES), Poly[imino(1,6-dioxohexamethylene) iminohexamethylene] (Nylon 6), poly(propylene) (PP), poly(ethylene) (PE), poly(urethane), perfluoroether (PFA), fluorinated ethylene propylene (FEP), ethylene vinyl acetate (EVA), poly(phenylsulfone) (PPSU), poly-n-butyl methacrylate, polyethylene-vinyl acetate, silicon and combinations thereof.

In some embodiments, the polymeric composition comprises at least one biodegradable or bioresorbable polymer including, without limitation, polylactic acid (PLA), poly(DL-lactide-co-caprolactone), poly(lactic co-glycolic acid), poly-D,L lactide, poly-l-lactic acid, polycaprolactone (PCL), poly(ester-amide), L-lactide/DL-lactide (PLDL), L-lactide/D-lactide (PLD), L-lactide/glycolide (PLG), L-lactide/caprolactone (PLC), DL-lactide/glycolide (PDLG), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(glycerol sebacate) (PGS), polyurethane urea (Artelon®), poly(ortho esters), poly(phosphoesters), poly(anhydrides), poly(carbonates), poly-(R)-3-hydroxybutyrate (P3HB), Polyhydroxybutyrate (PHB), Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), Polydioxanone (PDO, PDS), poly(trimethylene carbonate), poly(acrylates), poly(ethylene glycol) (PEG), poly(acetals), poly(ortho esters), polyphosphazenes, polyamides, collagen, silk, gelatin, hyaluronic acid, cross-linked biological tissue and derivatives thereof, cellulose, chitin, chitosan, alginates, dextran, pullulan, cyclodextrin and combinations thereof.

In some embodiments, the thermoelectric coil system 200 is configured to convert the temperature gradient exhibited by and between the thermoelectric coil system 200 and a biological tissue structure into electrical energy. In some embodiments, the thermoelectric coil system comprises a thermoelectric coil system disclosed in Nan, et al., Compliant and Stretchable Thermoelectric Coils for Energy Harvesting in Miniature Flexible Devices, Applied Sciences and Engineering, vol. 4, pp. 1-7 (2018), which is incorporated by reference herein in its entirety.

In some embodiments, the power supply means comprises a hybrid energy harvesting and storage system that comprises an energy harvesting system and one of the aforementioned harvesting systems and batteries, such as the hybrid energy harvesting and storage systems disclosed in Kim, et al., Research Update: Hybrid Energy Devices Combining Nanogenerators and Energy Storage Systems for Self-Charging Capability, APL Materials, vol. 5, pp. 1-12 (2017), which is incorporated by reference herein in its entirety.

In a preferred embodiment of the invention, the physiological sensor sub-system 3 is configured to at least partially biodegrade in vivo.

Referring now to FIG. 3, there is shown a schematic illustration of another embodiment of a biodegradable physiological sensor system 102 of the invention. As illustrated in FIG. 3, the biodegradable physiological sensor system 102 similarly comprises a physiological sensor sub-system 7, which, in this embodiment, includes an energy harvesting sensor 16, processing means 4 and signal transmitting means 6, and a remote device 12.

In some embodiments, the energy harvesting sensor 16 is configured to detect and measure at least one detectable physiological event associated with a monitored subject or physical aspect of a local environment when disposed proximate thereto and generate power for the physiological sensor system 100 by converting mechanical, chemical, electrical or thermal physiological processes into electrical energy.

In a preferred embodiment, the energy harvesting sensor 16 is configured to continuously and simultaneously detect and measure at least one detectable physiological event associated with a monitored subject or physical aspect of a local environment when disposed proximate thereto, and generate power for the physiological sensor sub-system 7 by converting mechanical, chemical, electrical or thermal physiological processes into electrical energy.

In a preferred embodiment of the invention, the energy harvesting sensor 16 comprises a biodegradable piezoelectric film, such as the aforementioned PLLA piezoelectric film.

In some embodiments, the energy harvesting sensor 16 comprises a biodegradable thermoelectric coil system comprising at least one biodegradable thermoelectric coil and a polymer film comprising a biodegradable polymer composition comprising at least one of the aforementioned polymers.

As indicated above, in a preferred embodiment of the invention, the tissue prostheses of the invention are configured to be positioned proximate a physiological structure of a subject; particularly, the subject's heart, and (i) induce modulated healing, e.g. inflammation modulation, remodeling of damaged tissue and regeneration of new tissue, and (ii) continuously monitor and detect physiological parameters associated therewith.

In some embodiments, when the tissue prostheses are positioned proximate a physiological structure of a subject, the tissue prostheses concurrently or substantially simultaneously (i) induce modulated healing, e.g. inflammation modulation, remodeling of damaged tissue and regeneration of new tissue, and (ii) continuously monitor and detect physiological parameters associated therewith.

Referring now to FIG. 4, there is shown an illustration of a human heart. As illustrated in FIG. 4, functionally, the heart is divided into two sides, i.e. right and left, or sections, i.e. pulmonary and systemic circulation sections. The right or pulmonary circulation section (designated “PCS”) receives blood from the veins of the body and pumps it through the lungs. The left or systemic circulation section (designated “SCS”) receives the blood from the lungs and pumps it to the body. The blood is then collected in the veins to be returned to the right side of the heart.

As illustrated in FIG. 4, the arterial system begins at the aorta 1, to which the left ventricle of the heart pumps. The aorta 1 passes down (caudad) through the body, providing arterial branches to organs, and terminates as a bifurcation, i.e. creating the iliac arteries. The first three branches of the aorta 1 are the brachiocephalic or innominate artery 2, the left (common) carotid artery 3, and the left subclavian artery 4. The brachiocephalic artery 2 branches into the right subclavian 5 and right (common) carotid arteries. These arteries provide the blood supply for the head and upper extremities.

As further illustrated in FIG. 4, the brachiocephalic or innominate artery 2 is the first branch of the aorta 1. The innominate artery 2, in turn, branches into the right subclavian 5 and right carotid arteries 6. In contrast, the left subclavian 4 and left carotid arteries 3 originate directly off the aortic arch. Thus, the subclavian 4 and carotid arteries 3, as well as their branches, have different paths from their counterparts on the opposite side of the body.

Referring now to FIG. 5, there is shown a graphical illustration of a cardiac cycle (or heart beat), showing cardiac events and changes in blood volume and pressure associated therewith. As is well known in the art, a cardiac cycle is one of a sequence of contractions (systole), which, as illustrated in FIG. 5, results in an increase in pressure and expelling of blood into the arteries, and relaxations (diastole), which results in a decrease in pressure and the filling of the heart chambers from the veins.

The cardiac cycle is typically divided into distinct periods, i.e. diastole and systole, which are determined by electrical and mechanical events, i.e. diastolic and systolic events. The noted periods and events associated therewith are discussed in detail below.

Diastole is the period during which the filling of the ventricles occurs. Diastole is typically divided into four intervals: isovolumic relaxation, early diastolic filling, diastasis and atrial contraction.

At the end of systole, the semi-lunar valves shut and the ventricles relax, resulting in a fall in the intraventricular pressure. This is an active process, known as the period of isovolumic relaxation. Isovolumic relaxation ends when the pressure in the ventricles decreases to below that in the atria and the AV valves open (see FIG. 5).

At resting heart rates, the majority of the filling of the ventricles occurs during early diastolic filling. Early diastolic filling is often deemed a “passive” period, when the blood stored in the atrial “priming” chambers flows rapidly into the ventricles. Early diastolic filling ends when the elastic properties of the ventricle(s) or myocardial muscle (i.e. sarcomere) prevent further filling (the length of the stretched sarcomere defining “preload”) and the pressure rises above that in the atria.

As illustrated in FIG. 5, diastasis is often the longest period in diastole. During diastasis, only a small amount of blood flows from the atria.

The second period of diastole, during which there is significant blood flow, is when the ventricles are actively filled by blood from atrial contraction. Atrial contraction includes a “pump-priming” action that increases the ventricular pressure immediately prior to systole.

Systole is the period during which the ventricles develop pressure to drive blood into the arteries. Systole is typically divided into three intervals: electromechanical delay, isovolumic contraction and the ejection period.

Electromechanical delay is the period of time taken for the electrical stimulus to result in activation of the ventricular muscle.

The period of isovolumic contraction is the period of time when the ventricles have begun to contract, but the volume of the chambers has not yet changed. It occurs immediately after the period of electromechanical delay, following electrical stimulation of the ventricles. During this period, intraventricular pressure increases until it is sufficient to open the semilunar valves and eject blood into the arteries.

As stated above, contractility is the index reflecting the intrinsic ability of the myocardial muscle to develop the necessary force to eject blood into the arteries.

The pre-ejection period (“PEP”) typically includes both the electromechanical delay and isovolumic contraction.

The ejection period occurs when the semilunar valves have opened, and the ventricles eject the forward stroke volume into the systemic circulation, i.e. into the ascending aorta. There is a short period during which the velocity of blood flow accelerates to a peak, after which there is a gradual decline until the point at which the aortic pressure is sufficiently high to prevent further ejection of blood.

As is well recognized in the art, cardiac stroke volume, i.e. the volume of blood ejected from the heart per unit of time, is a seminal index of cardiac performance, which is dependent on (or determined by) three cardiac parameters or factors; preload, afterload and contractility.

As is also well known in the art, in cardiac physiology, preload is the pressure stretching the ventricle of the heart, after atrial contraction and subsequent passive filling of the left ventricle. Preload is theoretically most accurately described as the initial stretching of a single cardiac myocyte prior to contraction. Preload cannot, however, be measured in vivo and therefore other measurements are used to estimates preload. Estimations are, however, typically inaccurate. For example, in a chronically dilated ventricle new sarcomeres may have formed in the heart muscle allowing the relaxed ventricle to appear enlarged.

The term end-diastolic volume is better suited to the clinic, although not exactly equivalent to the laboratory term preload.

For purposes of this disclosure, preload is thus employed as a volume term.

Coordinated contraction of cardiac muscle cells in the heart propel blood from the atria and ventricles to the blood vessels of the circulatory system. For purposes of this disclosure, contractility is thus employed as the force term to describe the ejection of blood from a ventricle.

As is further well known in the art, in cardiac physiology, afterload is used to mean the tension produced by a chamber of the heart in order to contract. If the chamber is not mentioned, it is usually assumed to be the left ventricle. However, the strict definition of the term relates to the properties of a single cardiac myocyte. It is therefore only of direct relevance in the laboratory. In the clinic, the term end-systolic pressure is usually more appropriate, although not equivalent.

Afterload can also be described as the pressure that the chamber of the heart must generate in order to eject blood out of the chamber, and thus is a consequence of the aortic pressure, since the pressure in the ventricle must be greater than the systemic pressure in order to open the aortic valve. Everything else held equal, as afterload increases, cardiac output decreases.

For purposes of this disclosure, afterload is thus employed to indicate impedance and resistance to blood flow.

As illustrated in FIG. 5, there are multiple cardiac function determinants (denoted CFD₁₋₁₅) that can, and in many instances will, affect the noted cardiac parameters, i.e. preload, afterload and contractility, and, hence, cardiac stroke volume. The determinants include ventricular geometric form, left ventricular stiffness, left ventricular end diastolic volume, venous return, right atrial pressure, health condition of the myocardium, endogenous and exogenous effectors (drugs and agents), valvular conditions, viscosity of the blood, central venous pressure, mean systemic pressure, arterial and aortic compliance and total peripheral resistance.

As is well known in the art, the cardiac function determinants can affect one of the cardiovascular parameters or multiple cardiovascular parameters, e.g., contractility and afterload.

In at least one embodiment of the invention, the physiological sensor systems of the invention, i.e. physiological sensor sub-systems thereof, such as physiological sensor sub-system 3 discussed above, is configured to detect and monitor at least one of the aforementioned cardiac function parameters.

As indicated above, in some embodiments of the invention, the physiological sensor sub-systems of the invention, including sensor sub-systems 3 and 7 discussed above, comprises a MEM accelerometer. In some embodiments the MEM accelerometer is specifically configured to detect and measure acceleration parameters associated with a heart, and, thereby, generate acceleration signals representing relative three-dimensional positioning of a predetermined cardiovascular structure of a subject's heart, e.g., the myocardium of the left ventricular wall, over a predetermined period of time.

According to the invention, the acceleration signals can be transmitted to remote device 12 and the acceleration parameters of the heart represented thereby can then be processed by remote device 12 to determine at least one cardiovascular parameter based on the contractility of the subject's heart.

In some embodiments of the invention, the remote device 12 is configured to process the acceleration parameters of the heart to determine heart velocity parameters derived therefrom. According to the invention, the heart velocity parameters can be derived from acceleration data signals using any conventional integration method.

Thus, in some embodiments of the invention, the method for determining at least one cardiovascular parameter of a subject's heart with the tissue prostheses of the invention generally comprises:

(i) providing a tissue prosthesis comprising a base structure and a physiological sensor system;

(ii) positioning the tissue prosthesis on a subject's heart, wherein the tissue prosthesis is positioned proximate the myocardium;

(iii) initiating the physiological sensor system of the tissue prosthesis;

(iv) detecting and measuring acceleration parameters of the subject's heart and, thereby, relative three-dimensional positioning of the myocardium of the subject's heart over a predetermined period of time;

(v) generating acceleration signals representing the measured acceleration parameters;

(vi) processing the acceleration signals;

(vii) transmitting the processed acceleration signals to the remote device;

(viii) determining the contractility of a subject's heart as a function of the processed acceleration signals with the remote device;

(ix) determining at least one cardiovascular parameter as a function of the determined contractility of a subject's heart with the remote device; and

(x) determining a cardiovascular parameter value as a function of the processed sensor signals with the remote device.

In some embodiments of the invention, the remote device is programmed and configured to generate and continuously update at least one diagnostic data set.

In a preferred embodiment, the diagnostic data set correlates at least one array of measured or determined anatomical acceleration parameters with at least one array of determined anatomical velocity parameters of a subject's myocardium.

Referring now to Table I, there is shown an illustration of one embodiment of a diagnostic data set for a subject. As illustrated in Table I, the diagnostic data set preferably comprises at least an array of measured or determined anatomical acceleration parameter values and anatomical velocity parameters measured at defined time points of a subject's myocardium during monitoring with a physiological sensor system of the invention.

TABLE I Subject #1 Time (t) Anatomical Acceleration (m/s²) Anatomical Velocity (cm/s) t₁ a₁ v₁ t₂ a₂ v₂ t₃ a₃ v₃ t₄ a₄ v₄ t₅ a₅ v₅ t₆ a₆ v₆ t₇ a₇ v₇

According to the invention, the diagnostic data set shown in Table I can be graphically presented and interpolated using any applicable methods and/or equations.

Referring now to FIG. 6, there is shown a graphical illustration of the diagnostic data set shown above as stacked correlating graphs showing the relationship between anatomical acceleration (a) and anatomical velocity (v) over a predetermined period of time.

As illustrated in FIG. 6, based on the graphical illustration of the diagnostic data set, the peak systolic velocity (denoted “v_(sys)”) and the period of isovolumetric relaxation (denoted “v_(IVR)”) of a subject's cardiac cycle can be determined.

In some embodiments, the piezoelectric MEM sensor is further configured to detect and measure locations and/or orientations of a predetermined cardiovascular structure of a subject's heart. According to the invention, the detected and measured locations and/or orientations of the cardiovascular structure can be used to determine contractility of the subject's heart. In some embodiments, the detected and measured locations and/or orientations are processed by remote device 12 to form a three-dimensional, time-dependent map of the heart.

As indicated above, in some embodiments of the invention, the physiological sensor sub-systems of the invention comprise a MEM strain gauge. In some embodiments the MEM strain gauge is specifically configured to monitor strain differences of a predetermined cardiovascular structure of a subject's heart during at least one cardiac cycle. According to the invention, the detected and measured strain differences can then be processed by remote device 12 to determine the contractility of the subject's heart.

According to the invention, the physiological sensor systems of the invention can be configured to detect, measure and/or monitor at least one physiological characteristic or parameter of various other physiological structures of a subject, e.g., lungs, liver and musculoskeletal system.

Thus, in some embodiments of the invention, the method for determining at least one physiological parameter of a subject's physiological structure with the tissue prostheses of the invention generally comprises:

(i) providing a tissue prosthesis comprising a base structure and a physiological sensor system;

(ii) positioning the tissue prosthesis on a subject's physiological structure;

(iii) initiating the physiological sensor system of the tissue prosthesis;

(iv) detecting and measuring physiological parameters over a predetermined period of time;

(v) generating sensor signals representing the measured physiological parameters;

(vi) processing the sensor signals;

(vii) transmitting the processed sensor signals to the remote device;

(viii) determining a physiological parameter as a function of the processed sensor signals with the remote device; and

(ix) determining a physiological parameter value as a function of the processed sensor signals with the remote device.

Referring now to Table II, there is shown summary of seminal physiological structures, associated tissue, and associated physiological parameters or characteristics that the physiological sensor systems of the invention can be configured to detect and measure. In a preferred embodiment, the physiological sensor systems of the invention are further configured to determine the referenced physiological structure abnormalities as a function of the physiological characteristics or parameters.

TABLE II Structure Physiological Associated Structural (Substructure) Tissue Characteristic(s) Abnormalities Cardiovascular Myocardial, Cardiac tissue Myocardial infarction Myocardium including contractility, i.e. Chronic heart failure (CHF) Pericardium Epicardial myocardial tension Cardiac arrhythmias, including, Pericardial development (dT/dt) without limitation, atrial Cardiac tissue action fibrillation (Afib), sinus potential (mV) bradycardia, premature atrial Pulse rate contractions, wandering atrial Electrical activity pacemaker, atrial tachycardia, (EKG), e.g., preload, multifocal atrial tachycardia, afterload, stroke supraventricular tachycardia volume (SVT), atrial flutter, AV nodal reentrant tachycardia, junctional rhythm, junctional tachycardia, premature junctional contraction, premature ventricular contractions (PVCs), accelerated idioventricular rhythm, monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, ventricular fibrillation and torsades de pointes. Cardiomyopathies, including, without limitation, myocarditis- associated cardiomyopathy, ischemic cardiomyopathy and eosinophilic myocarditis- associated cardiomyopathy. Cardiovascular Valvular Blood flow rate (L/min) Valve stenosis, including, Valves Systolic/diastolic blood without limitation, aortic valve pressure (mmHg) stenosis, mitral valve stenosis, Pulse rate tricuspid valve stenosis and Electrical activity pulmonary valve stenosis. (EKG) Valve insufficiency/regurgitation, including, without limitation, aortic, mitral, tricuspid and pulmonary valve insufficiency/regurgitation. Cardiovascular Vascular, i.e. Blood flow rate (L/min) Peripheral artery disease Vessels arteries and Systolic/diastolic blood (PAD) veins, pressure (mmHg) Venous thrombosis, including, including, Vascular contractility, without limitation, deep vein atrial and i.e. smooth muscle thrombosis, portal vein venous tension development thrombosis, renal vein (dT/dt) thrombosis, cerebral venous sinus thrombosis, jugular vein thrombosis and cavernous sinus thrombosis. Arterial thrombosis, including, without limitation, thrombotic stroke and thrombosis- associated myocardial infarction. Gastrointestinal Intestinal Smooth muscle Congenital and auto-immune (GI) system Stomach contractility GI diseases, including, Intestines Esophageal Blood oxygen without limitation, ulcerative Stomach Pancreatic content colitis, Crohn's disease and Pancreas Gallbladder Local fluid pH inflammatory bowel disease. Gallbladder Hepatic Local immune GI cancers, including, Liver response without limitation, intestinal Metabolite content cancer, stomach cancer, pancreatic cancer and liver cancer. Gastric and peptic ulcers Gastritis Gastroenteritis Cholecystitis Liver cirrhosis Urinary system Urinary Smooth muscle Urinary system cancers, Bladder bladder contractility including, without limitation, Kidneys Renal Blood oxygen bladder cancer and kidney content cancer. Local fluid pH Hunner's ulcer, i.e. bladder Local immune ulcer. response Nephritis Metabolite content Urethritis Renal failure Respiratory Alveolar Smooth muscle Respiratory organ system Bronchi contractility cancers, including, Lungs Tracheal Blood oxygen content without limitation, lung Larynx Local fluid pH cancer and tracheal Immune response cancer. Gas pressure Respiratory infections, Gas composition including, without limitation bronchitis, pneumonia and tuberculosis. Restrictive lung diseases, including, without limitation, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). Dermal system Dermal Tissue contractility Dermal cancers, Skin Immune response including, without limitation, melanoma, basal-cell skin cancer and squamous-cell skin cancer.

As indicated above, in a preferred embodiment of the invention, upon delivery of a tissue prosthesis of the invention; particularly, a tissue prosthesis comprising a base structure comprising an ECM composition or ECM/PGS composition or ECM/polymer composition, proximate damaged tissue of a subject, the base structure of the prosthesis remodels, modulates inflammation of the damaged tissue, and induces remodeling of the damaged tissue and regeneration of new tissue and tissue structures, and the physiological sensor system monitors physiological characteristics of the subject.

Referring now to FIGS. 7 and 8, there is shown one embodiment of a tissue prosthesis of the invention (denoted “20”). As illustrated in FIGS. 7 and 8, the tissue prosthesis 20 comprises a base structure or member 22, comprising a sheet structure or layer, and physiological sensor sub-system of the invention (denoted “3′”). In the illustrated embodiment, the base member 22 is preferably in a folded configuration to facilitate encasing the physiological sensor system 3′ therein.

In some embodiments, the base member 22 is configured to encase a plurality of physiological sensor sub-systems of the invention.

As set forth in priority U.S. application Ser. No. 13/573,566, now U.S. Pat. No. 9,066,993, which is incorporated by reference herein in its entirety, in a preferred embodiment, the base member 22 comprises an ECM composition of the invention.

As also set forth in priority U.S. application Ser. No. 13/573,566, the base member 22 can also include more than one sheet structure or layer, e.g., two (2), three (3) sheet layers, etc. The sheet layers can also comprise the same material, i.e. ECM composition, or different materials or compositions, including any of the aforementioned ECM compositions and/or ECM-mimicking compositions and/or ECM/PGS compositions and/or polymeric compositions and/or ECM/polymeric compositions.

Referring now to FIG. 9 there is shown another embodiment of a tissue prosthesis of the invention (denoted “25 a”). As illustrated in FIG. 7, the tissue prosthesis 25 a comprises a planar base structure 24 a, comprising top and bottom surfaces 23 a, 23 b, and a physiological sensor sub-system 3′ of the invention, which, in the illustrated embodiment, is disposed proximate, more preferably, secured to the top surface 23 a.

According to the invention, the physiological sensor sub-system 3′ can also be secured to the bottom surface 23 b.

In some embodiments, the tissue prosthesis 25 a comprises a plurality of physiological sensor sub-systems 3′.

According to the invention, the plurality of physiological sensor sub-systems 3′ can also be secured to the top surface 23 a, bottom surface 23 b or both the top and bottom surfaces 23 a, 23 b of tissue prosthesis 25 a.

According to the invention, the physiological sensor sub-system(s) 3′ can be secured to the tissue prosthesis 25 a using any conventional method. In some embodiments, the physiological sensor sub-system(s) 3′ is at least partially embedded into the tissue prosthesis 25 a.

In some embodiments, the physiological sensor sub-system(s) 3′ is adhered to the tissue prosthesis 25 a using an adhesive composition. According to the invention, suitable adhesive compositions include, without limitation, poly(glycerol sebacate) (PGS), poly(glycerol sebacate) acrylate (PGSA), fibrin-based compositions and collagen-based compositions.

According to the invention, the tissue prosthesis 25 a can similarly include more than one sheet layer, e.g., two (2) or three (3) sheet layers. The sheet layers can also comprise the same material, i.e. ECM composition, or different materials or compositions.

Referring now to FIG. 10 there is shown another embodiment of a tissue prosthesis of the invention (denoted “25 b”). As illustrated in FIG. 10, the tissue prosthesis 25 b similarly comprises a planar base structure 24 b, comprising top and bottom surfaces 28 a, 28 b, and a physiological sensor sub-system 3′ of the invention.

As further illustrated in FIG. 10, at least one surface of the planar base structure 24 b, in this instance, the bottom surface 28 b, comprises a plurality of microneedles 27 that are designed and configured to engage a biological tissue structure and maintain contact therewith for a pre-determined period of time, such as disclosed in Applicant's U.S. Pat. No. 8,778,012, which is incorporated by reference herein in its entirety.

According to the invention, the microneedles 27 can comprise any of the aforementioned compositions, e.g., an ECM composition, ECM-mimicking composition, ECM/PGS composition, polymeric composition and ECM/polymeric composition.

As described in detail in U.S. Pat. No. 8,778,012, the microneedles 27 can further comprise at least one of the aforementioned biologically active agents and/or pharmacologically active agents.

The microneedles 27 can also comprise hollow microneedle members that are configured to deliver at least one of the aforementioned biologically active agents and/or pharmacologically active agents to biological tissue when disposed proximate thereto.

In some embodiments, the physiological sensor sub-system 3′ is secured to the micro-needle tissue prosthesis 25 b using at least one of the aforementioned adhesive compositions.

Referring now to FIGS. 11-13, there is shown another embodiment of a tissue prosthesis of the invention (denoted “30”). As illustrated in FIG. 11, the tissue prosthesis comprises a base structure 32 and a physiological sensor sub-system 3′ of the invention.

As further illustrated in FIG. 11, the base structure comprises two (2) sheet structures or layers 15 a, 15 b that are joined together to form a laminate sheet structure.

In a preferred embodiment, the sheet layers 15 a, 15 b are preferably joined on at least one of the ends 19 a, 19 b, more preferably, the sheet layers 15 a, 15 b are joined on at least both ends 19 a, 19 b.

According to the invention, the sheet layers 15 a, 15 b can be joined (or laminated) by various conventional means, such as stitching, including ECM stitches, staples and adhesives. The sheet layers 15 a, 15 b can also be laminated via microneedles and/or microneedle structures, such as disclosed in U.S. Pat. No. 8,778,012.

As also illustrated in FIG. 13, the sheet layers 15 a, 15 b are preferably sized, configured and positioned to receive the physiological sensor sub-system 3′ therebetween.

In some embodiments, the sheet layers 15 a, 15 b are sized, configured and positioned to receive a plurality of physiological sensor sub-system(s) 3′ therebetween.

According to the invention, the base structure 32 can similarly include more than two sheet layers, e.g., three (3) or four (4) sheet layers. The sheet layers can also comprise the same material, i.e. ECM composition, or different materials or compositions, including any of the aforementioned compositions of the invention.

Referring now to FIGS. 14A and 14B, there is shown yet another embodiment of a tissue prosthesis of the invention (denoted “40”). As illustrated in FIGS. 14A and 14B, the tissue prosthesis 40 also comprises a base structure 41 and a physiological sensor sub-system 3′ of the invention.

As further illustrated in FIGS. 14A and 14B, the base structure 41, in this embodiment, comprises a two-piece valve structure, such as disclosed in Applicant's U.S. Pat. No. 8,709,076, which is incorporated by reference herein.

As set forth in Applicant's U.S. Pat. No. 8,709,076 and illustrated in FIGS. 14A and 14B, the base structure 41, i.e. two-piece valve structure, comprises first and second valve members 42, 46 comprising first and second internal lumen lumens 43 a, 43 b, respectively.

As further illustrated in FIGS. 14A and 14B, in one embodiment of the invention, the physiological sensor sub-system 3′ is secured to the second internal lumen 43 b of the second valve member 46.

According to the invention, the physiological sensor sub-system 3′ can be secured to the second valve member 46 using any conventional method. In some embodiments, the physiological sensor sub-system 3′ is secured to the second internal lumen 43 b using at least one of the aforementioned adhesive compositions.

In some embodiments, a plurality of physiological sensor sub-systems 3′ are secured to the second internal lumen 43 b of second valve member 46.

In some embodiments, the physiological sensor sub-system 3′ is secured to the first internal lumen 43 a of the first valve member 42. In some embodiments, a plurality of physiological sensor sub-systems 3′ are secured to first internal lumen 43 a of the first valve member 42.

According to the invention one or more physiological sensor sub-systems 3′ can also be disposed proximate the outer surfaces of the first and/or second valve members 42, 46.

Referring now to FIGS. 15A and 15B, there is shown yet another embodiment of a tissue prosthesis of the invention (denoted “60”). As illustrated in FIGS. 15A and 15B, the tissue prosthesis 60 also comprises a base structure 61 and a physiological sensor sub-system 3′ of the invention.

As further illustrated in FIGS. 15A and 15B, the base structure 61, in this embodiment, comprises a seamless tubular valve structure, such as disclosed in Applicant's U.S. Pat. No. 9,011,526, which is incorporated by reference herein.

As set forth in U.S. Pat. No. 9,011,526 and illustrated in FIGS. 15A and 15B, the base structure 61, i.e. tubular valve structure, comprises an internal lumen 69 that extends therethrough, outer and inner surfaces 63, 65, first and second ends 62, 64, and, as discussed in detail in U.S. Pat. No. 9,011,526, at least one flow modulating internal valve leaflet 65.

In a preferred embodiment, the physiological sensor sub-system 3′ is secured to the internal lumen 69 of base structure 61. According to the invention, the physiological sensor sub-system 3′ can be secured to the internal lumen 69 of base structure 61 by any conventional method.

In a preferred embodiment, the physiological sensor sub-system 3′ is secured to the internal lumen 69 using at least one of the aforementioned adhesive compositions.

In some embodiments, a plurality of the physiological sensor sub-systems 3′ are secured to the internal lumen 69 of base structure 61.

According to the invention, one or more physiological sensor sub-systems 3′ can also be disposed proximate the outer surface 63 of the base structure 61.

Referring now to FIG. 16, there is shown yet another embodiment of a tissue prosthesis of the invention (denoted “70”). As illustrated in FIG. 16, the tissue prosthesis 70 similarly comprises a base structure 71 and a physiological sensor sub-system 3′ of the invention.

As further illustrated in FIG. 16, the base structure 71, in this embodiment, comprises a conical valve structure, such as disclosed in Applicant's U.S. Pat. No. 10,188,509, which is incorporated by reference herein.

As discussed in detail in U.S. Pat. No. 10,188,509 and illustrated in FIG. 16, the base structure 71, i.e. conical valve structure, comprises an open proximal end 72, closed distal end 74, an inner surface 71 and an outer surface 73, and a plurality of flow modulating interstices 76 a-76 d.

In a preferred embodiment, the physiological sensor sub-system 3′ is secured to the inner surface 78 of base structure 71. According to the invention, the physiological sensor sub-system 3′ can similarly be secured to the inner surface 78 of base structure 71 by any conventional method, including, without limitation, one of the aforementioned adhesive compositions.

In some embodiments, a plurality of the physiological sensor sub-systems 3′ are secured to the inner surface 78 of base structure 71.

According to the invention, one or more physiological sensor sub-systems 3′ can also be disposed proximate the outer surface 73 of the base structure 71.

According to the invention, the physiological sensor sub-systems 3′ of the invention can be configured to be incorporated into any base valve structure to form a tissue prosthesis of the invention, including, without limitation, the valve structures disclosed in Applicant's U.S. Pat. Nos. 9,044,319, 9,308,084, 9,907,649, 10,188,510, 10,052,409, 10,188,513, 8,257,434, 8,409,275, 8,679,176, 8,449,607, 8,608,796, 7,998,196, 8,790,397, 8,696,744, 9,241,789, 8,845,719, 9,226,821 and Co-pending U.S. application Ser. Nos. 16/129,968, 15/877,629, 16/193,669 and 16/238,730, which are incorporated herein in their entirety.

The physiological sensor sub-systems 3′ of the invention can also be configured to be incorporated into a base structure comprising a cardiovascular prosthesis to form a tissue prosthesis of the invention, including, without limitation, the cardiovascular prostheses disclosed in Applicant's U.S. Pat. Nos. 10,143,778, 10,201,636, 9,867,906, 9,919,079 and Co-pending U.S. application Ser. Nos. 15/877,586 and 16/130,020, which are incorporated herein in their entirety.

The physiological sensor sub-systems 3′ of the invention can also be configured to be incorporated into a base structure comprising a vascular prosthesis to form a tissue prosthesis of the invention, including, without limitation, the vascular prostheses disclosed in Applicant's U.S. Pat. Nos. 8,808,363, 9,694,105, 9,694,104, 9,744,261, 9,352,070, 9,433,491, 10,052,189, 9,533,072, 9,498,559, 9,737,399, 9,867,696 and Co-pending U.S. application Ser. No. 15/835,714, which are incorporated herein in their entirety.

As indicated above, the base structures 22, 24 a, 24 b, 32, 41, 61 and 71 of the tissue prostheses 20, 25 a, 25 b, 30, 40, 60 and 70 described above can comprise one of the aforementioned compositions, i.e. an ECM composition, ECM-mimicking composition, polymeric composition, ECM/PGS composition, and ECM/polymeric composition.

As will readily be appreciated by one having ordinary skill in the art, the present invention provides numerous advantages compared to prior art prostheses. Among the advantages are the following:

-   -   The provision of tissue prostheses that substantially reduce or         eliminate (i) the risk of thrombosis, (ii) intimal hyperplasia         after intervention in a vessel, (iii) the harsh biological         responses associated with conventional polymeric and metal         prostheses, and (iv) the formation of biofilm, when delivered to         damaged tissue; particularly, damaged cardiovascular tissue.     -   The provision of tissue prostheses that modulate inflammation         and induce host tissue proliferation, remodeling and         regeneration of new tissue and tissue structures with         site-specific structural and functional properties, when         delivered to damaged tissue.     -   The provision of tissue prostheses that are capable of         administering a pharmacological agent to host tissue and,         thereby produce a desired biological and/or therapeutic effect.     -   The provision of implantable physiological sensor systems that         are capable of accurately monitoring seminal physiological         characteristics of a subject over extended periods of time.     -   The provision of tissue prostheses that (i) remodel, modulate         inflammation of damaged tissue and induce host tissue         proliferation, remodeling and regeneration of new tissue and         tissue structures with site-specific structural and functional         properties, and (ii) monitor seminal physiological         characteristics of a subject over extended periods of time.

Without departing from the spirit and scope of this invention, one of ordinary skill can make various changes and modifications to the invention to adapt it to various usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of any subsequently proffered claims. 

What is claimed is:
 1. A tissue prosthesis, comprising: a base structure and a physiological sensor system, said physiological sensor system being joined to said base structure, said base structure comprising an extracellular matrix (ECM) composition comprising acellular ECM from a mammalian tissue source, said base structure, when disposed proximate damaged biological tissue, being adapted to induce modulated healing of said damaged tissue, said modulated healing comprising reducing an inflammatory phase of said damaged tissue and inducing host tissue proliferation, bioremodeling and, thereby, neovascularization of said damaged tissue, and regeneration of new tissue and tissue structures, said base structure and physiological sensor system being jointly adapted to concurrently induce said modulated healing and detect at least one physiological parameter of said subject, when disposed proximate said damaged biological tissue of said subject.
 2. The tissue prosthesis of claim 1, wherein said mammalian tissue source comprises mammalian tissue selected from the group consisting of small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), urinary basement membrane (UBM), liver basement membrane (LBM), amniotic membrane, mesothelial tissue, placental tissue and cardiac tissue.
 3. The tissue prosthesis of claim 1, wherein said ECM composition further comprises an additional biologically active agent.
 4. The tissue prosthesis of claim 3, wherein said biologically active agent comprises a growth factor selected from the group consisting of a basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF).
 5. The tissue prosthesis of claim 1, wherein said ECM composition further comprises a pharmacological agent selected from the group consisting of antibiotics, anti-arrhythmic agents, anti-viral agents, analgesics, anti-inflammatory agents, anti-neoplastics, anti-spasmodics, antithrombotic agents, and vasodilating agents.
 6. The tissue prosthesis of claim 1, wherein said ECM composition further comprises poly(glycerol sebacate) (PGS).
 7. The tissue prosthesis of claim 1, wherein said base structure comprises a sheet structure.
 8. The tissue prosthesis of claim 1, wherein said base structure comprises a prosthetic valve structure.
 9. The tissue prosthesis of claim 1, wherein said physiological sensor system is biodegradable.
 10. The tissue prosthesis of claim 1, wherein said at least one physiological parameter of said subject comprises a physiological parameter selected from the group consisting of tissue contractility, tissue action potential, electrical activity, blood pressure, fluid pH, blood oxygen content and immune response.
 11. A tissue prosthesis, comprising: a base structure and a physiological sensor system, said physiological sensor system being joined to said base structure, said base structure comprising a polymeric composition comprising at least one biodegradable polymer, said physiological sensor system being adapted to detect at least one physiological parameter of said subject in vivo.
 12. The tissue prosthesis of claim 11, wherein said at least one biodegradable polymer comprises a polymer selected from the group consisting of polylactic acid (PLA), poly(DL-lactide-co-caprolactone), poly(lactic co-glycolic acid), poly-D,L lactide, poly-l-lactic acid, polycaprolactone (PCL), poly(ester-amide), L-lactide/DL-lactide (PLDL), L-lactide/D-lactide (PLD), L-lactide/glycolide (PLG), L-lactide/caprolactone (PLC), DL-lactide/glycolide (PDLG), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(glycerol sebacate) (PGS), and poly(urethane urea).
 13. The tissue prosthesis of claim 11, wherein said polymer composition further comprises a pharmacological agent selected from the group consisting of antibiotics, anti-arrhythmic agents, anti-viral agents, analgesics, anti-inflammatory agents, anti-neoplastics, anti-spasmodics, antithrombotic agents, and vasodilating agents.
 14. The tissue prosthesis of claim 11, wherein said base structure comprises a sheet structure.
 15. The tissue prosthesis of claim 11, wherein said base structure comprises a prosthetic valve structure.
 16. The tissue prosthesis of claim 11, wherein said at least one physiological parameter of said subject comprises a physiological parameter selected from the group consisting of tissue contractility, tissue action potential, electrical activity, blood pressure, fluid pH, blood oxygen content and immune response. 